Adoptive transfer of simian immunodeficiency virus (SIV) naı̈ve autologous CD4+ cells to macaques chronically infected with SIV is sufficient to induce long-term nonprogressor status

Abstract

IntroductionAlthough highly active antiretroviral therapy (HAART) has a major beneficial effect on HIV-1-infected individuals, 1,2 it is clear that the next major therapeutic breakthrough requires a better definition of strategies for full immune reconstitution. 3 One of the challenges in achieving this goal is our lack of understanding of the precise spectrum or kinetics of the development of immune dysfunction in individual HIV-infected patients and strategies best suited to reconstitute such immune defects. Although virus-specific cytotoxic T lymphocytes (CTLs) clearly play a major role in eliminating virus-infected cells, 4-6 development and maintenance of such CTL pools require CD4 ϩ T helper cell function and an appropriate balance of cytokines. 3,7,8 It is also clear that innate immune mechanisms play a major role particularly during the initial stages of infection, 9,10 influencing the viral load set point, and that virus-neutralizing antibodies contribute to the containment of cell-free virus infection of naive cells. 11,12 Thus, a variety of immune reconstitution strategies need to be explored, some of which may be of benefit to those patients who were initiated on HAART during acute infection, whereas others may be more appropriate to patients with chronic infection. Since the primary target of HIV-1 infection is the CD4 ϩ T cells and the depletion of those cells is one of the major consequences of infection, our laboratory has initially focused on seeking methodologies for the replenishment of this cell lineage.Several studies aimed at immune reconstitution have previously been performed utilizing autologous unfractionated and in vitro expanded CD8 ϩ T cells from HIV-1-infected patients. [13][14][15] Transient decreases in viral load and increases in CD4 ϩ T-cell counts have been achieved utilizing such immune reconstitution therapies. However, these studies used autologous cells collected after HIV infection. Thus, lack of a more profound effect could be due to either an abnormal microenvironment for the adoptively transferred cells to home, survive, and/or execute immune function, or an intrinsic defect in the transferred T cells, as a direct and/or indirect effect of the virus infection. Clearly, a number of defects ranging from loss of lymphocyte specificities and subsets to signaling defects of CD4 ϩ T cells from HIV-1-infected patients have been documented. [16][17][18][19][20] Yet definitive proof for such defects cannot be obtained from the study of humans infected with HIV-1, since it would involve the use of autologous cells obtained prior For personal use only. on May 10, 2018. by guest www.bloodjournal.org From to infection. Hence, such mechanistic questions require the use of an animal model, which provides infection-induced immune dysfunction within an immune system comparable to humans. Simian immunodeficiency virus (SIV)-infected nonhuman primates provide such a model, in which we may attempt to distinguish among the above-mentioned 2 possibilities since the CD4 ϩ T cells can be colle...

Containment of Simian Immunodeficiency Virus Infection in Vaccinated Macaques: Correlation with the Magnitude of Virus-Specific Pre- and Postchallenge CD4+ and CD8+ T Cell Responses

“…Preservation of CD4 ϩ T cells may provide sufficient helper activity for APCs and maintain CTL function. Recent data demonstrate that adoptive transfer of naive autologous CD4 ϩ T cells to chronically SIVmac-infected rhesus macaques promoted virus-specific CTL responses and induced long-term control of virus replication, and further support a key role of CD4 ϩ Th cells in the control of infection (21). Moreover, virus-specific CD4 ϩ responses are vigorous in macaques infected with live attenuated SIV that are protected against heterologous challenge (52).…”

“…In rhesus macaques, the extent of virus-specific LPR induced by therapeutic vaccination of SIVmac-infected antiretroviral therapy-treated animals correlated with the containment of viremia after drug withdrawal (20,54). Moreover, adoptive transfer of naive autologous CD4 ϩ T cells in SIVmac-infected macaques resulted in an increase of virus-specific CTL responses and long-term viremia containment, suggesting a defect in the Th cell compartment rather than the effector cell compartment (21).…”

CD8+-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment

“…However, chronic viremia was suppressed more efficiently during tenofovir treatment when less-virulent SIV isolates were used (52,76,80) or when tenofovir treatment was combined with other antiviral drugs and/or immunotherapy strategies (17,21,36,95).…”

Structured Treatment Interruptions with Tenofovir Monotherapy for Simian Immunodeficiency Virus-Infected Newborn Macaques

“…Several other macaque studies that used a single treatment course or a regimen with multiple interruptions were more effective in inducing a lower viremia set point in a larger proportion of the animals (23,24,29,31,32,34,(54)(55)(56)74). A combination of factors is likely to be responsible for this difference in success rate, as these other studies used (i) older animals, (ii) less-virulent virus isolates (i.e., isolates that induce lower viral RNA set points in untreated animals or that, following suppression of acute viremia, are easier to control immunologically), (iii) combination drug regimens with a longer initial treatment period, or (iv) a combination of antiviral drug treatment with immunotherapeutic strategies (e.g., immunization and adoptive cell transfer).…”